tbuckley/cabot-search huggingface dataset:
Abstract 2038: Epstein-Barr virus shapes the tumor microenvironment in classical Hodgkin lymphoma
Authors: Maryam Pourmaleki, Caitlin J. Jones, Sabrina D. Mellinghoff, Brian Greenstein, Priyadarshini Kumar, Mikhail Roshal, Travis J. Hollmann, Nicholas D. Socci, Ahmet Dogan, Ingo K. Mellinghoff
Journal: Cancer Research (2023)

Abstract The histopathologic appearance of classical Hodgkin lymphoma (cHL) is characterized by rare multinucleated malignant Hodgkin Reed-Sternberg (HRS) cells within a rich inflammatory tumor microenvironment (TME). A subset of cHL cases are associated with Epstein-Barr virus (EBV) infection, which is considered to play a part in cHL pathogenesis. Since EBV+ and EBV- cHL exhibit differing mechanisms of pathogenesis, we hypothesized that the composition and spatial architecture of the TME in EBV-associated cHL differs from that of EBV- cHL, with implications for stratifying patients for specific treatment regimens based on EBV positivity. Here, we designed a multimodal approach using spatially resolved multiplexed protein profiling, flow cytometry, immunohistochemistry, and transcriptomics to profile EBV positive and EBV negative cHL tumors. We measured over 27 million single cells and 1,000 unique proteomic cell states derived using 29 proteins in addition to the transcriptome in 43 patient tumors. We uncovered significant differences between EBV+ and EBV- cHL in relative abundance of specific immune cell types, immune activation state, and spatial organization of the HRS cell neighborhoods. We present a multidimensional characterization of cHL in relation to EBV with implications for therapeutic stratification of patients with virus-associated cHL. Citation Format: Maryam Pourmaleki, Caitlin J. Jones, Sabrina D. Mellinghoff, Brian Greenstein, Priyadarshini Kumar, Mikhail Roshal, Travis J. Hollmann, Nicholas D. Socci, Ahmet Dogan, Ingo K. Mellinghoff. Epstein-Barr virus shapes the tumor microenvironment in classical Hodgkin lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2038.
Abstract 1232: Gastroesophageal reflux disease promotes E-cadherin cleavage and activates EMT via APE1-redox function in esophageal adenocarcinoma
Authors: Heng Lu, Longlong Cao, Farah Ballout, Abbes Belkhiri, Dunfa Peng, Lei Chen, Mohammed Soutto, Oliver McDonald, Alexander Zaika, Jianwen Que, Wael El-Rifai
Journal: Cancer Research (2023)

Abstract The incidence of esophageal adenocarcinoma (EAC) has increased rapidly over the past four decades. Chronic gastroesophageal reflux disease (GERD), where acidic bile salts (ABS) abnormally refluxate into the esophagus, is the leading risk factor for the development of a metaplastic condition known as Barrett’s esophagus (BE) and its progression to EAC. We used 3D organotypic culture, mouse and human tissue samples to assess the role of ABS in Epithelial-to-Mesenchymal Transition (EMT) in EAC. Analysis of public databases revealed significant enrichment of EMT signaling in EAC progression. RNA-seq analysis of EAC cells showed activation of EMT pathway in response to ABS exposure. ABS induced multiple characteristics of the EMT process, such as downregulation of E-cadherin, upregulation of Vimentin, activation of ß-catenin and EMT-transcription factors (EMT-TFs), cell morphological changes, and enhancement of cell migration and invasion capabilities. Mechanistically, we discovered that ABS induced E-cadherin cleavage via MMP14 proteolytic cascade. APE1 silencing, or APE1-redox-specific inhibitor (E3330), abrogated the ABS-induced EMT process and signaling by downregulating MMP14. Furthermore, APE1 and MMP14 co-expression levels were inversely correlated with E-cadherin expression in gastroesophageal junctions of human EAC tissues, and the L2-IL1ß transgenic mouse model of BE/EAC. EAC patients with high APE1 and EMT signatures had worse relapse free survival than those with low signature. In a summary, this study demonstrates the role of ABS in promoting EMT via the redox-sensitive signaling axis of APE1/MMP14/E-cadherin/ß-catenin. Pharmacological inhibition of APE1-redox function could be a potential therapeutic approach to effectively reduce the risk of Barrett’s carcinogenesis. Citation Format: Heng Lu, Longlong Cao, Farah Ballout, Abbes Belkhiri, Dunfa Peng, Lei Chen, Mohammed Soutto, Oliver McDonald, Alexander Zaika, Jianwen Que, Wael El-Rifai. Gastroesophageal reflux disease promotes E-cadherin cleavage and activates EMT via APE1-redox function in esophageal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1232.
Abstract 6522: Improved detection of low frequency mutations in ovarian and endometrial cancers by utilizing a highly accurate sequencing platform
Authors: Jiannis Ragoussis, Nairi Pezeshkian, Lucy Gilbert
Journal: Cancer Research (2023)

Abstract Ovarian and endometrial cancers come within the top-4 for incident cancers as well as deaths in North American women. Cure rates have not improved in 30 years as high-grade subtypes continue to be diagnosed in Stage III/IV. Attempts at early diagnosis have failed because high-grade cancer cells exfoliate and metastasize while the primary cancer is small and undetectable by existing tests based on imaging and blood-based tumour markers. DOvEEgene (Detecting Ovarian and Endometrial cancers Early using genomics) is a genomic uterine pap test developed by a McGill team to screen and detect these cancers while they are confined to the gynecologic organs and curable by surgery. The test identifies pathogenic somatic mutations in uterine brush samples A high sensitivity error-reducing capture technology (DOvEEgene-SureSelectHS) utilizing duplex sequencing interrogates the exons of 23 genes involved in the development of sporadic and hereditary ovarian and endometrial cancers. We apply a combination of germline gene panel testing on saliva samples with deep duplex sequencing to detect somatic mutations at &amp;lt;0.1% VAF, interrogation of microsatellite loci for instability and low coverage WGS for copy number analysis of uterine brush samples. Currently, DOvEEgene is the only test that can discriminate ovarian and endometrial cancers in peri- and postmenopausal women from benign gynecologic diseases common in that age group. This is important because pathogenic somatic driver mutations are also associated with increasing age and benign disease. DOvEEgene incorporates a deep machine-learning derived classifier that can discriminate the mutational signature of these cancers from benign disease aiming for a sensitivity of 70% and a specificity of 100% in a population with high background mutational burden. Here we tested the Onso system, a highly accurate sequencing technology from PacBio in order to potentially increase sensitivity while driving down sequencing costs by reducing required sequencing depth vs the current NGS standard. We sequenced 15 duplex Illumina sequencing libraries produced using the DovEE assay at PE 100bp mode and compared Onso data in non- duplex sequencing mode as well as duplex sequencing mode to the original duplex sequencing method. Here, we present this comparison and highlight the benefits of high accuracy sequencing for the detection of very low frequency (&amp;lt;0.1%) somatic mutations. Citation Format: Jiannis Ragoussis, Nairi Pezeshkian, Lucy Gilbert. Improved detection of low frequency mutations in ovarian and endometrial cancers by utilizing a highly accurate sequencing platform [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6522.
Abstract 4993: Development of abbapolin inhibitors of the PLK1 PBD as potential therapeutics for prostate and other challenging cancers
Authors: Jessy Stafford, Danda Chapagai, George Merhej, Justin Pressley, Chintada Nageswara-Rao, Michael Wyatt, Campbell Mcinnes
Journal: Cancer Research (2023)

Abstract Polo-like kinase 1 (PLK1) has a plethora of roles within the cell of which mitotic regulation is the best characterized. This kinase is overexpressed and upregulated in cancer cells, making it an attractive target for therapeutics. Drug discovery efforts have mainly focused on the ATP binding site however have met with little clinical success to date. Targeting substrate recognition and subcellular localization through the Polo-Box domain represents an attractive alternative to generating PLK1 specific compounds and to avoid the tumor suppressor functions of PLK3. REplacement with Partial Ligand Alternatives through Computational Enrichment, REPLACE, is validated strategy used to convert peptide inhibitors of protein-protein interactions into more drug like compounds. Through the use of this methodology, we have discovered promising non-ATP competitive inhibitors based on a 2-(4-AlkylBenzamido) Benzoic Acid (ABBA) pharmacophore which bind to the polo-box domain of PLK1. These compounds, designated as abbapolins, engage PLK1 as evidenced by their ability to block phosphorylation of TCTP, a key substrate of PLK1, induce PLK1 degradation and are potently anti-proliferative in prostate cancer cell lines. Based on these observations, lead compounds were investigated further for their pharmacokinetic properties and in vivo efficacy and key compounds showed development potential based upon preliminary results. To further investigate their potential in other tumors, selected abbapolins were tested against the NCI-60 tumor cell panel and other cancers with poor prognosis. Results indicate that neuroblastoma, lung, colorectal and certain leukemias are the most sensitive cell lines and thus provide impetus to investigate the abbapolins for difficult to treat and resistant tumors. We present the further optimization of the abbapolins to determine their structure-activity relationship and identify compounds with novel structures and improved drug-like properties. This includes their ability to engage PLK1 and anti-proliferative activities against selected cell lines that represent therapeutically challenging cancers. Furthermore, these compounds serve as chemical biology probes to elucidate roles of the PBD in conformationally regulating PLK1 activity, through in vitro experiments and specifically in the abbapolin sensitive cell lines. Citation Format: Jessy Stafford, Danda Chapagai, George Merhej, Justin Pressley, Chintada Nageswara-Rao, Michael Wyatt, Campbell Mcinnes. Development of abbapolin inhibitors of the PLK1 PBD as potential therapeutics for prostate and other challenging cancers. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4993.
Abstract 5631: Expanding tools for multiplex mRNA imaging in spatialomics through the ViewRNA tissue assay kits
Authors: Nancie Mooney
Journal: Cancer Research (2023)

Abstract Spatialomics is a rapidly growing field as it allows researchers to gain a deeper understanding of transcriptomes and corresponding protein expression profiles in cells within complex tissue microenvironments. One critical technology for spatialomics is in-situ hybridization (ISH) technology, which enables direct visualization and quantitation of nucleic acid in cells with single molecule resolution. The Invitrogen ViewRNA ISH assays incorporate branched DNA (bDNA) technology provides tools for interrogating multiple RNA transcripts at the same time, paving the way for improved spatialomics research. This technology is a powerful tool for spatialomics, giving insight into important mechanisms within cells and tissue. With researchers increasingly using spatialomic data in fields like neuroscience, immuno-oncology &amp; single-cell analysis, these scientists will need the rapid and efficient detection of mRNA co-expression profiles that ViewRNA portfolio provides. In our newest offering, ViewRNA fluorescence tissue kits we extended our branched DNA technology, proprietary probe set design and signal amplification technology with Alexa Fluor probes offering a unique, robust, and sensitive in situ hybridization assay for RNA localization in fixed tissues. With fluorescence detection using Alexa Fluor 488, Alexa Fluor 546, Alexa Fluor 594, Alexa Fluor 647, and Alexa Fluor 750, these kits allow multiplexed detection and imaging paving the way for improved spatialomics. This technology lays the foundation for expanded fluorescent profiles to provide scientists additional tools to probe multiple transcripts per sample, allow broader spatialomics research. For Research Use Only. Not for use in diagnostic procedures. Citation Format: Nancie Mooney. Expanding tools for multiplex mRNA imaging in spatialomics through the ViewRNA tissue assay kits. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5631.
Abstract 1161: Primary and metastatic tumors exhibit systems-level differences in dependence on mitochondrial respiratory function
Authors: Neal K. Bennett, Hiroki J. Nakaoka, Danny Laurent, Ross Okimoto, Yoshitaka Sei, Andrew E. Horvai, Trever G. Bivona, Georgios Batsios, Pavithra Viswanath, Johanna ten Hoeve, Thomas G. Graeber, Ken Nakamura, Jean L. Nakamura
Journal: Cancer Research (2023)

Abstract The Warburg effect, aerobic glycolysis, is a hallmark feature of cancer cells grown in culture. However, the relative roles of glycolysis and respiratory metabolism in supporting in vivo tumor growth and processes such as tumor dissemination and metastatic growth remain poorly understood, particularly on a systems level. Using a CRISPRi mini-library enriched for mitochondrial ribosomal protein and respiratory chain genes in multiple human lung cancer cell lines we analyzed in vivo metabolic requirements in xenograft tumors grown in distinct anatomic contexts. While knockdown of mitochondrial ribosomal protein and respiratory chain genes (mito-respiratory genes) has little impact on growth in vitro, tumor cells depend heavily on these genes when grown in vivo as either flank or primary orthotopic lung tumor xenografts. In contrast, respiratory function is comparatively dispensable for metastatic tumor growth. RNA-Seq and metabolomics analysis of tumor cells expressing individual sgRNAs against mito-respiratory genes indicate overexpression of glycolytic genes and increased sensitivity of glycolytic inhibition compared to control when grown in vitro, but when grown in vivo as primary tumors these cells downregulate glycolytic mechanisms. Metabolic shifts associated with silencing mito-respiratory genes can be detected in vivo with metabolic imaging. These studies demonstrate that discrete perturbations of mitochondrial respiratory chain function impact in vivo tumor growth in a context-specific manner with differential impacts on primary and metastatic tumors. Citation Format: Neal K. Bennett, Hiroki J. Nakaoka, Danny Laurent, Ross Okimoto, Yoshitaka Sei, Andrew E. Horvai, Trever G. Bivona, Georgios Batsios, Pavithra Viswanath, Johanna ten Hoeve, Thomas G. Graeber, Ken Nakamura, Jean L. Nakamura. Primary and metastatic tumors exhibit systems-level differences in dependence on mitochondrial respiratory function [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1161.
Abstract 1513: A multi-sample study reveals the evolution and heterogeneity in high-grade serous ovarian cancer
Authors: Siao-Han Wong, Kai Doberstein, Frederik Marmé, Benedikt Brors
Journal: Cancer Research (2023)

Abstract Ovarian cancer is a heterogeneous disease and high-grade serous carcinoma (HGSC) accounts for 70% of them. The pathogenesis of HGSC had remained obscure until the identification of its tubal origin; however, the carcinogenesis process remains largely underexplored. Meanwhile, targeted therapy using poly(ADP-ribose) polymerase (PARP) inhibitors have revolutionized the treatment of HGSCs and emphasizes the importance of patient stratification. Nonetheless, current clinical trials use different assays and a consensus approach for patient stratification is still lacking. In this study, whole genome sequencing technique was used to profile tumor-normal sample pairs, including some related tumors collected from different anatomical sites. This yields a multi-sample cohort comprising 55 pre-treatment samples from 33 HGSC patients and is suitable for addressing questions about molecular stratification and tumor pathogenesis. We first recapitulated two reported HGSC subgroups (H-HRD and H-FBI) in our cohort. Comprehensive analyses were conducted on genomic scars ranging from mutations, indels, structural variants and copy numbers. Our data suggests that the genomic subgroups are characterized by different extent and onset timing of homologous recombination repair defect (HRD) as well as CCNE1 activation. Of note, H-HRD group showed higher levels of copy number-based HRD score, which often serves as a surrogate biomarker for PARP inhibitor treatment response. On the other hand, tumor evolutionary trajectory was reconstructed based on in silico methods capable of inferring relative timing of genetic alterations. This highlights an early bifurcation of carcinogenesis paths in this HGSC dichotomy, despite a common scenario of a very early TP53 mutation, an often early whole genome duplication and a chromosomal instability phenotype seen eventually. Overall, these findings corroborate the concept of tumor-intrinsic genomic phenotypes by providing mechanistic underpinnings from the aspect of tumor evolution. This provides the rationale for studying HGSC disease biology in different contexts and formulating questions about subtype-specific pathogenesis and vulnerabilities. Translationally, it also holds the promise for better identifying the patient subset that might benefit from PARP inhibitor treatment. Citation Format: Siao-Han Wong, Kai Doberstein, Frederik Marmé, Benedikt Brors. A multi-sample study reveals the evolution and heterogeneity in high-grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1513.
Abstract 2547: YAP1 associates with the EPHA3 receptor tyrosine kinase to promote prostate cancer progression
Authors: Marwah M. Al-Mathkour, Abdulrahman M. Dwead, Kezhan Khazaw, Bekir Cinar
Journal: Cancer Research (2023)

Abstract Metastatic castration-resistant prostate cancer is lethal, and the mechanisms contributing to this deadly disease are largely unknown. The disparity in our knowledge poses a significant barrier to developing effective therapeutics against advanced prostate cancer in humans. Evidence suggests that the ephrin family of receptor tyrosine kinase signaling may play a critical role in the pathobiology of prostate cancer progression. However, the mechanism is elusive. Our initial study showed that YAP1, in concert with the TEAD1 transcription factor, regulated EPHA3 expression. However, the significance of EPHA3 signaling in prostate cancer remains elusive. Here we investigated the role of EPHA3 signaling in prostate cancer cells. We showed that the expression of EPHA3 correlated with YAP1 in prostate cancer clinical samples. We also showed that EPHA3 knockout reduced cell growth in 2D and 3D cultures. In addition, EPHA3 loss sensitized castration-resistant prostate cancer cells to enzalutamide. Moreover, EPHA3 knockout reduced the GTPase activity of RHOA compared to cells with EPHA3-WT, which coincided with reduced phospho-ERK1/2 levels. Consistently, EPHA3 knockout reduces phosphor-ERK1/2, similar to the inhibition of phospho-ERK1/2 by an inhibitor of ROCK1 (Rho-associated coiled-coil-containing protein kinase 1). Besides, EPHA3 knockout reduced the expression of EMT markers ZEB1/2 and the cancer stem cell marker CD44 compared to the wild type. Furthermore, the levels of EPAH3 transcripts were higher in high-grade PC of AA patients compared to other races. Finally, AA and Caucasian Americans (CA) PC cell lines differentially express the member of ephrin-A and ephrin-B receptors. These observations suggest that the YAP1-EPHA3 signaling is a viable therapeutic target for patients with advanced prostate cancer. Citation Format: Marwah M. Al-Mathkour, Abdulrahman M. Dwead, Kezhan Khazaw, Bekir Cinar. YAP1 associates with the EPHA3 receptor tyrosine kinase to promote prostate cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2547.
Abstract 4995: Targeting PLK1 effectively suppresses growth of small cell lung cancer
Authors: John C. Schmitz, Guojing Zhang, Andrey A. Ivanov, Abbe Pannucci, Maya Ridinger, Taofeek K. Owonikoko
Journal: Cancer Research (2023)

Abstract Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumor characterized by rapid disease progression and poor patient survival. Key transcription factors implicated as drivers of unique biological phenotypes of SCLC include ASCL1, NEUROD1, YAP1, and POU2F3. Strategies to exploit these phenotypes for innovative precision medicine approaches will be impactful. Using an unbiased agnostic preclinical drug screen to uncover therapeutic opportunities in SCLC, we identified a strong signal with PLK1 inhibitors (PLK1i) with low nanomolar IC50. We extended the in vitro findings by testing the efficacy of PLK1i in vivo using traditional xenograft of SCLC H526 cell line and patient derived xenografts (PDX). Volasertib achieved significant tumor growth inhibition relative to control in H526 xenografts. Also, onvansertib significantly inhibited growth of platinum-resistant and platinum-sensitive PDXs. The combination of PLK1i with standard chemotherapeutic agents identified promising synergy of the combination of onvansertib and paclitaxel. We further interrogated for predictive biomarkers of PLK1i sensitivity using gene expression profile comparing highly sensitive to less sensitive cell lines. High expression of C-MYC but not PLK1, TP53 or RB was associated with resistance to PLK1i. Conversely, while TP53 expression level did not correlate, TP53 gene mutation status (inactivating disruptive mutations) correlated with cell sensitivity to PLK1i. We queried the publicly available CCLE and the Cancer Therapeutics Response Portal to evaluate whether any of the SCLC subtypes have therapeutic vulnerability to PLK1i. In general, high expression of YAP1 in SCLC cell lines correlated with greater sensitivity to PLK1i. A YAP1 positive cell line, SW1271, with strong TP53 expression was particularly resistant to PLK1i. CRISPR knockout of YAP1 in this cell line enhanced SW1271 sensitivity to PLK1i suggesting that YAP1 expression as a marker of vulnerability to PLK1i could be context dependent especially when co-occurring with TP53 mutations. The mechanism of this interaction will be discussed. Citation Format: John C. Schmitz, Guojing Zhang, Andrey A. Ivanov, Abbe Pannucci, Maya Ridinger, Taofeek K. Owonikoko. Targeting PLK1 effectively suppresses growth of small cell lung cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4995.